In order to examine the effect of DENV C on induction of type-I interferon, expression vectors were constructed encoding either immature or mature forms of the DENV C protein. After overexpression of DENV C, HEK293 cells were treated with poly(I:C) and induction of antiviral activity was determined by measuring virus titers after infection with VSV. Overexpression of DENV C leads to an elevation of virus titers, indicating a reduction in antiviral activity. HEK293 cells overexpressing DENV C displayed decreased induction of interferon beta after treatment with poly(I:C) when compared to mock transfected controls. Mutations introduced to the amino-terminus of the DENV C gene resulted in a decreased ability to influence induction of interferon beta compared to wild-type counterparts. Host Interaction partners for DENV C were identified by co-Immunoprecipitation (co-IP) followed by mass spectrometry (MS). MS identified a number of potential interaction partners, including Nucleolin (NCL). DENV C interactions with NCL were also characterized. DENV C was shown to directly interact with NCL via FRET and through the use of purified recombinant proteins. Knockdown of NCL with siRNA, or blocking the interaction between the C protein and NCL by treating cells with a NCL binding aptamer (AS1411), resulted in a significant reduction of viral titers after DENV infection. Western blot and qRT-PCR analysis revealed no differences in viral RNA or protein levels at early time points post-infection, suggesting a role for NCL in viral morphogenesis. We have supported this hypothesis by showing that treatment with AS1411 alters the migration characteristics of the viral capsid as visualized by native electrophoresis, as well as the accessibility of viral RNA to amplification by RT-PCR. Our data suggests a critical interaction between DENV C protein and NCL, which represents a potential new target for the development of antiviral therapeutics. Our current work involves the further characterization of host DENV C interaction partners as well as the identification of novel pathways involved in DENV mediated subversion of the innate immune response.